In 1977, mitocondorial benzogeazepin receptor (hereafter, it is abbreviated as MBR.) was identified as a receptor that is different from a benzodiazepine binding site in GABAA receptor to which benzodiazepines bind (“Science 198, 849-851, 1977”; “Proc. Natl. Acad. Sci., 89, 3805-3809, 1977”), it has been reported to take part in steroid synthesis, the differentiation and proliferation of cell, and the immune function modulate, etc. though a physiological function is not necessarily clarified. In peripheral tissue, there are MBR in immune system cells such as red blood cell, platelet, monocyte, and macrophages beside adrenal cortex, heart, smooth muscle, kidney, lungs, testis, and in plexus chorioideus, pineal body, olfactory bulb, cerebral cortex, and hippocampus, etc. of central nervous system. Expressing cells in central nervous system has been known to be glia cells mainly, it may be used as a marker of gliosis so that the expression may increase along with the neurodegenerative diseases such as alzheimer's disease, cerebral ischemia, multiple sclerosis, and huntington's disease, etc.
It has been reported that when exposed to chronic stressors, morphologic changes like neuronal death in CA3 field and the shrinkage of dendrite, etc. is admitted in hippocampus and that the number of glial fibrillary acidic protein positive cells increases (Stress, 3, 275-284, 2000). It has been suggested that the activation of MBR could happen in glia cells at stress.
There are MBR in mitochondrial outer membrane, which transports cholesterol from intracellular to the internal membrane of mitochondria that is the active site of P-450 scc. Steroid synthesized in encephalon is called as neurosteroid, cholesterol, which is the steroid precursor, is converted into pregnenolone with side chain cleavage enzyme P-450 scc in the first stage of steroidogenesis system. However, it has been presented that this transport process rather than in the metabolism by P-450 scc is a limiting in the steroid production system. It has been thought that the content of neurosteroid in encephalon can be adjusted if the function of MBR can be adjusted. Actually, it has been reported that a diazepam binding inhibitory protein (diazepam binding inhibitor; hereafter, it might be abbreviated as DBI.) identified as an endogenous ligand of MBR and a benzodiazepine binding site in GABAA receptor promoted the pregnenolone synthesis at mitochondrial fraction from rat brain and glioma cells.
It has been presented that DBI content increases in hippocampus by load sound stressor to rat and DBI density in cerebrospinal fluid of depression patients rises, and is expected that the amount of neurosteroid production could increase at stress. It is reported that the contents of various neurosteroids increase in encephalon by load stressors such as forced swimming, foot shock, expose of carbon dioxide, and restriction as experimental results that proves this.
Neurosteroid adjusts the function of various receptors and ion channels positively or negatively according to the type. For example, though pregnenolone sulfate and dehydroepiandrosterone sulfate control the function of GABAA receptor, progesterone activats that. And, though pregnenolone sulfate controls functions of AMPA/kainic acid-type glutamate receptor, glycine receptor, and voltage-dependent calcium channel, on the other hand, activates the function of NMDA-type glutamate receptor. Progesterone controls the function of acetylcholine receptor together with glycine receptor. In addition, progesterone is oppositely controled though dehydroepiandrosterone sulfate activates the function of σ receptor. It has been thought that the change of activity of nervous system, immune system, and endocrine system variously adjusted with these nervous systems and the development of diseases related to various stresses could be caused to the collapse of balance between an excitatory signal transmission system and an inhibitory one by the shift of the amount of neurosteroid in encephalon at stress. Considering reports that pregnenolone sulfate reinforces NMDA induced cell death of culture hippocampal neurones and causes late cell death with DNA fragmentation in neural retina cells, the possibility that pregnenolone sulfate also takes part in the degeneration of hippocampus CA3 field at stress partially at least is suggested.
As mentioned above, the inhibition of increase of neurosteroid production via anomalously activated MBR by stressor load and the recovery of balance between the excitatory signal transmission system and the inhibitory one to be normal are effective for the treatment of the disease related to stress. Therefor, it is expected that MBR antagonists could be extremely useful for prevention and treatment of these diseases.
The following compounds are known as 1-carbamoyl-1-benzazepine compound.
(A) It has been described that compounds represented by formula (A)
and non-toxic salt thereof are useful as tranquilizer in U.S. Pat. No. 3,748,321 specification.
The following compounds are concretely indicated.
(A-1) 1-(N-2-dimethylaminoethyl-N-methylcarbamoyl)-4-phenyl-2,3,4,5-tetrahydros-1H-1-benzazepine hydrochloride (CAS No. 50832-30-9)
(A-2) N-[2-(dimethylamino)ethyl]-3,4-dihydro-N-methyl-2-phenyl-1,5-benzoxazepine-5-(2H)-carboxamide hydrochloride (CAS No. 50689-70-8)
(B) It has been described that compounds represented by formula (B)
are useful as a diuretic, a hypoglycemic agent, anti-bacteria medicine, and an anticonvulsant in U.S. Pat. No. 3,458,498 specification.
Concretely, the following compounds have been described.
(B-1) 1-cyclohexylcarbamoyl-7-methoxy-2,3,4,5-tetrahydros-1H-1-benzazepine (CAS No. 23605-96-1)
(B-2) 7-methoxy-1-phenylcarbamoyl-2,3,4,5-tetrahydro-1H-1-benzazepine (CAS No. 23573-35-5)
(B-3) 1-butylcarbamoyl-7-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine (CAS No. 23561-99-1)
(C) A Compound Represented by Formula (C)
has been described in FR1473839 specification as a intermediate.
Concretely, the following compounds are indicated.
(C-1) 1-propylcarbamoyl-2,3,4,5-tetrahydro-1H-1-benzazepine (CAS No. 17422-51-4)
(D) The compounds represented by formula (D)
have been described as fibrinogen antagonists in WO93/00095 specification.(E) The compounds represented by formula (E)
have been described as endothelin antagonists in WO95/04534 specification.
However, 1-carbamoyl-1-benzazepine compound is not concretely indicated in a patent publication in which the compounds represented by formula (D) and (E) have been described.
(F) In J. Chem. Soc. Perkin Trans 1 (1992), (24), 3401-6,
(F-1) 7-acetyl-1-methylcarbamoyl-2,3,4,5-tetrahydro-1H-1-benzazepine (CAS No. 147265-78-9)
(F-2) 1-methylcarbamoyl-2,3,4,5-tetrahydro-1H-1-benzazepine(CAS No. 147265-72-3)
have been described.(G) In J. Med. Chem. 1967, 10(5)944-5,(G-1) 1-carbamoyl-3-phenyl-2,3,4,5-tetrahydro-1H-1-benzazepine (CAS No. 16967-72-9)
have been described.
However, so far, it has not been known at all that 1-carbamoyl-1-benzazepine compound has MBR competitive activity.